The focus of this proposal is on the role of the cyclin D1 oncogene in oral cancer. Oropharyngeal squamous cell carcinomas (OSCC) are aggressive tumors that result in significant mortality and morbidity. Frequently, these tumors initiate as a precancerous lesion that develops to an invasive neoplasm. However, the molecular mechanisms underlying the transition to invasive neoplasia are not fully understood. Furthermore, the role of dietary agents in modifying this process has not been studied. The cyclin D1 oncogene plays an important role in OSCC development. Cyclin D1 is a key regulator of the G1-S phase of the cell cycle. Acting via its kinase partners CDK4 and CDK6, it results in phosphorylation of the retinoblastoma protein to effect cell cycle progression. The current paradigm assumes that this is the major mechanism of cyclin D1's oncogenic actions. However, there is emerging evidence that cyclin D1 participates in transcriptional control. We recently discovered that cyclin D1 binds to the vitamin D receptor (VDR) and modulates vitamin D signaling. This finding is particularly significant in that vitamin D plays an essential role in regulation of keratinocyte proliferation and differentiation. The studies described in this proposa will study the intersection between the cyclin D1 and vitamin D signaling pathways. The short-term goals of this proposal are to (1) examine the mechanism by which cyclin D1 deregulates vitamin D signaling and (2) examine role of dietary vitamin D deficiency in modulating the development of oral pre-cancer and cancer. The long-term goal is to study the contribution of vitamin D signaling in oral keratinocyte physiology and pathophysiology, its intersection with oncogenic pathways and its implications for oral carcinogenesis. To achieve these goals two Specific Aims are proposed. Specific Aim 1 will investigate the mechanism by which cyclin D1 deregulates VDR-mediated transcriptional control. Specific Aim 2 will examine the role of dietary vitamin D deficiency in modulating cyclin D1-driven oral pre-cancer using a transgenic mouse model system. These studies will significantly increase our understanding of cyclin D1's oncogenic mechanisms and vitamin D's role in modulating oral cancer risk. Given the emerging problem of vitamin D nutritional status both in the United States as well as globally, our studies have tremendous implications for potential dietary and chemopreventive approaches to oral cancer management. Furthermore, cyclin D1 is an established oncogene for several tumor types and there is growing evidence for vitamin D's role in several cancers. Thus, our studies have potentially broad implications for several other tumors types.